Pharmacogenomic Evaluation of Antihypertensive Responses

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Dr. Julie A Johnson, National Institute of General Medical Sciences (NIGMS)
ClinicalTrials.gov Identifier:
NCT00246519
First received: October 27, 2005
Last updated: July 8, 2013
Last verified: July 2013

October 27, 2005
July 8, 2013
October 2005
December 2010   (final data collection date for primary outcome measure)
Blood Pressure Response (Delta BP (After 18 Weeks of Medication - Baseline)). [ Time Frame: baseline to 18 weeks of treatment ] [ Designated as safety issue: No ]
blood pressure response
Complete list of historical versions of study NCT00246519 on ClinicalTrials.gov Archive Site
Adverse Metabolic Responses [ Time Frame: 9-18 weeks of treatment ] [ Designated as safety issue: Yes ]
adverse metabolic responses
Not Provided
Not Provided
 
Pharmacogenomic Evaluation of Antihypertensive Responses
Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR)

There are many medications available for the treatment of high blood pressure (hypertension), but finding the right one for a specific patient can be challenging. In fact, it is estimated that only 34% of people with hypertension have their blood pressure under control. The hypothesis is that genetic differences between individuals influence their response to antihypertensive medications. This study is aimed at determining the genetic factors that may influence a person's response to either a beta-blocker or a thiazide diuretic. The hope is that through this research, we may someday be able to use an individual's genetic information to guide the selection of their blood pressure medicine, leading to better control of blood pressure, and less need for the current trial and error process.

The proposed work should help move toward the long-term goal of selection of antihypertensive drug therapy based on a patient's genetic make-up. Hypertension (HTN) is the most common chronic disease for which drugs are prescribed, and the most prevalent risk factor for heart attack, stroke, renal failure and heart failure. Responses to antihypertensive drug therapy exhibit considerable interpatient variability, contributing to poor rates of HTN control (currently 34% in the US), and frequent nonadherence and dropout from therapy. We propose to identify genetic predictors of the antihypertensive and adverse metabolic responses to two preferred and pharmacodynamically contrasting drugs, a beta-blocker (atenolol) and a thiazide diuretic (HCTZ) given initially as monotherapy, and subsequently in combination, to 800 individuals with uncomplicated hypertension. High quality phenotype data, including both home and ambulatory measures of blood pressure (BP) response, and lipid and insulin sensitivity measures of adverse metabolic responses will be related to genetic variation through two approaches. First, testing 7 SNPs in each of 70 candidate genes, we will examine the influence of these genes' variation on responses to beta-blockers and diuretics (Specific Aim 1). This will include assessment of genetic associations with: antihypertensive responses to monotherapy (Aim 1a), addition of a second drug to monotherapy (Aim 1b), and combination therapy (Aim 1c); and adverse metabolic responses to mono and combination therapy (Aim 1d). This candidate gene approach will be supplemented by discovery of novel genes involved in variable BP and metabolic responses to beta-blockers and diuretics through testing of 20,000 putative functional SNPs that span the human genome (Specific Aim 2). As in Aim 1, Aim 2 will include testing for associations with antihypertensive and adverse metabolic responses to monotherapy and combination therapy. The proposed research will substantially increase our understanding of the pharmacogenetics of mono- and combination antihypertensive drug therapy. It will also lead to creation of data sets and samples that can be used by others in the field, through deposit of data to PharmGKB, and creation of immortalized cell lines from all study participants to share data and biological samples with other researchers. The proposed research is significant because genetically-targeted antihypertensive therapy could lead to dramatically higher response rates and fewer adverse effects than the usual trial-and-error approach. This would likely lead to higher rates of HTN control, less need for polypharmacy, reduced health care costs, and improved outcomes.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Hypertension
  • Drug: HCTZ + atenolol
    atenolol 50 or 100 mg hydrochlorothiazide 12.5 or 25 mg
    Other Names:
    • Aquazide H or HydroDIURIL or Microzide
    • Lopressor
  • Drug: Atenolol + HCTZ
    atenolol 50 mg, then 100 mg if BP < 120/70, then add HCTZ 12.5 mg if BP < 120/70, then HCTZ 25 mg if BP < 120/70
    Other Names:
    • Lopressor
    • Aquazide H or HydroDIURIL or Microzide
  • Experimental: Atenolol +HCTZ arm
    atenolol 50 mg, then 100 mg if BP < 120/70, then add HCTZ 12.5 mg if BP < 120/70, then HCTZ 25 mg if BP < 120/70
    Intervention: Drug: Atenolol + HCTZ
  • Experimental: HCTZ + atenolol
    HCTZ 12.5 mg then HCTZ 25 mg if BP < 120/70, then add atenolol 50 mg if BP < 120/70, then atenolol 100 mg if BP < 120/70.
    Intervention: Drug: HCTZ + atenolol

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
1701
December 2010
December 2010   (final data collection date for primary outcome measure)

Inclusion Criteria:

An average seated home DBP > 85 mmHg and home SBP < 180 mmHg. Subjects must also have an average seated (> 5 minutes) clinic DBP between 90 mmHg and 110 mmHg and SBP < 180 mmHg

Exclusion Criteria:

secondary forms of HTN, patients currently treated with three or more antihypertensive drugs, isolated systolic HTN, other diseases requiring treatment with BP lowering medications, heart rate < 55 beats/min, known cardiovascular disease (including history of angina pectoris, heart failure, presence of a cardiac pacemaker, history of myocardial infarction or revascularization procedure, or cerebrovascular disease, including stroke and TIA), diabetes mellitus (Type 1 or 2), renal insufficiency (serum creatinine > 1.5 in men or 1.4 in women), primary renal disease, pregnancy or lactation, liver enzymes > 2.5 upper limits of normal, current treatment with NSAIDS, COX2-inhibitors, oral contraceptives or estrogen.

Both
17 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00246519
U01 GM074492
Yes
Dr. Julie A Johnson, National Institute of General Medical Sciences (NIGMS)
National Institute of General Medical Sciences (NIGMS)
Not Provided
Principal Investigator: Julie A Johnson, PharmD University of Florida
National Institute of General Medical Sciences (NIGMS)
July 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP